1. Field of the Invention
The present invention relates to a novel conjugate of a phenylalanine derivative with an antitumor substance, a process for preparation thereof, and a pharmaceutical composition, in particular, an antitumor agent, containing it. More particularly, the present invention relates to a conjugate of L-phenylalanine-glycine with an antitumor substance, a process for preparation thereof, and a pharmaceutical composition containing it.
2. Description of the Related Art
Hitherto, chemotherapeutic agents have proved efficacious in treating tumors, but many problems still remain. For example, chemotherapeutic agents not only have effects on tumor cells, but also affect the host cells and exhibit cell toxicity. Therefore, the agents cannot be administered for a long time to physically weakened patients and thus it was difficult to secure a sufficient therapeutic effect. The mechanism of action of chemotherapeutic agents is based on the inhibition of biosynthesis (in particular, that of nucleic acids) in the cells and inhibition of the metabolism necessary to maintain cell life. That is, the chemotherapeutic agents were not specific to the tumor. Namely, these agents were toxic to the general cells of the host suffering from the tumor as well as toxic to the tumor cells. It was desired to develop antitumor agents with an improved selectivity to the tumor cells and an improved method for concentrating conventional antitumor agents into the tumor cells.
While, 5-fluorouracil (5-FU) alone does not exhibit antitumor activity, 5-FU exhibits antitumor activity when bonded with penrose phosphate in the cells to form fluorodeoxyuridine-5'-monophosphate (FdUMP), fluorouridine-5'-triphosphate (FUTP) or the like. Namely, FdUMP inhibits the thymidylate synthetase activity to inhibit the synthesis of DNA. FUTP is taken up in an RNA and causes critical damage to the RNA, thereby inhibiting the production of cell proteins. Therefore, if the penrose phosphate in the tumor cells could be increased selectively, selective chemotherapy to tumor cells would become possible by using 5-FU.
Further, pyruvate kinase is the rate-determining enzyme in the anaerobic glycolysis which relates to the production of penrose phosphate in the cells, and includes L-type, M.sub.1 -type, and M.sub.2 -type isoenzymes. Tumors contain almost only M.sub.2 -type isoenzyme. It was known that the M.sub.2 -type isoenzyme is selectively inhibited by a low concentration of L-phenylalanine. Therefore, it was expected that L-phenylalanine could cause inhibition specific to the pyruvate kinase activity in the tumor cells and enhance the production of penrose phosphate only in the tumor cells. Thus, Lee disclosed and ascertained a method of enhancing the activity of 5-FU to inhibit the tumor in combination with L-phenylalanine [Med. J. Kagoshima Univ., Vol. 37, No. 3-4, 285-308, 1985].
In the method of Lee, however, L-phenylalanine was mixed in a laboratory chew and ingested. 5-FU was separately administered. Therefore, L-phenylalanine and 5-FU were conveyed separately to the lesion. The present inventors engaged in various studies with the object of conveying L-phenylalanine and 5-FU to the target lesion in a bonded form and separating them quickly at the target site. As a result, the inventors found that the above object can be achieved by bonding 5-FU with L-phenylalanine-1-acetoxyglycine, and that there is a similar effect in antitumor substances other than 5-FU. The present invention is based on these findings.